As a developing Physician Scientist, my career goal is to cultivate and integrate my experience as a clinician and investigator so that I may ultimately translate a basic understanding of normal physiology and the disease process to the bedside. I am committed to a career in academic medicine with the goal of developing an internationally recognized phosphate homeostasis. The studies outlined in this proposal will allow me to apply and extend my clinical and technical training to a new level by broadening my experience in protein biochemistry, transgenic technology and antibody and radioimmunoassay development. Intensive laboratory investigation will be complimented by course work in the program of Cellular and Molecular Medicine. The Johns Hopkins Medical Institute provides a rich environment for collaboration and technical support both at an institutional level and within the Levine laboratory. Dr. Michael Levine is an internationally recognized expert in bone and mineral metabolism with a strong mentorship track record. He is the previous Director of the Johns Hopkins Institutional Physician Scientist Award and he is the current Director of the Training Program in Cellular and Molecular Endocrinology. Additional mentored laboratory based work and the specific career development plan Dr. Levine and I have devised will provide me with the skills I need to launch an independent research career. The research proposal I have prepared is an extension of my clinical interest in the molecular basis of hormone action, ectopic hormonal production and the regulation of phosphate homeostasis. Oncogenic osteomalacia (OOM) is a paraneoplastic syndrome characterized by hypophosphatemia, hypophosphaturia and osteomalacia. Tumors associated with OOM secrete a factor, termed phosphatonin (PTN) that inhibits renal proximal tubular reabsorption of phosphate. X-linked hypophosphatemic rickets (XLH) is a genetic syndrome with clinical manifestations similar to OOM. The defective gene in XLH encodes PEX, a membrane bound metallopeptidase. Other enzymes in this class have important roles in hormonal processing and degradation. The discovery of the defective PE enzyme paired with evidence for a circulating phosphaturic factor in both XLH and OOM, has led to speculation about the relationship of PEX and PTN. We hypothesize that phosphatonin is important for phosphate homeostasis in the bone and once phospatonin is related into the circulation, it exerts a phosphaturic effect on the proximal renal tubule. Phosphatonin is released into the circulation by either being produced ectopically as in OOM or by failing to be inactivated as in XLH. We propose to: 1) Isolate phosphatonin 2) Determine the role of PEX in phosphate homeostasis and its interaction with phosphatonin 3) Define the role of phosphatonin in normal physiology and in disorders of phosphate homeostasis. Identifying and characterizing phosphatonin will contribute substantially to the understanding of phosphate homeostasis, further define the genetic defect in X-linked hypophosphatemic rickets, and identify a novel hormone produced ectopically in oncogenic osteomalacia.